Dihydro-oxo-pyrido[1,2-a]thienopyrimidine compounds

ABSTRACT

Oxo-pyrido[1,2-a]thienopyrimidine compounds, salts thereof, methods of production, intermediates in their production, pharmaceutical compositions containing said compounds and methods for treating allergies using said compositions are disclosed.

This is a division, of application Ser. No. 070,227 filed Aug. 27, 1979,now U.S. Pat. No. 4,230,707.

SUMMARY AND DETAILED DESCRIPTION

The present invention relates to new oxo-pyrido[1,2-a]-thienopyrimidinecompounds that are useful as anti-allergy agents, intermediates in theirproduction, methods for their production, pharmaceutical compositionscontaining said anti-allergy agents and methods for treating allergicconditions with said compositions. More particularly, the inventionrelates to new oxo-pyridio[1,2-a]thienopyrimidine compounds of theformulae. ##STR1## and salts thereof, where R and R¹ are hydrogen, loweralkyl, chloro, bromo, phenyl, or X-substituted phenyl where X is loweralkyl, chloro, fluoro, or lower alkyl-O- and Z is ##STR2## wherein Y is--OH, --NH₂, --O-- lower alkyl or ##STR3##

The term "lower alkyl" is intended to mean a hydrocarbon moiety whichmay be straight, branched or cyclic in configuration having from one tosix carbon atoms.

The term "salts" is intended to mean salts formed by the addition of abase with those compounds of the invention capable of forming a salt,such as those compounds containing a carboxy or tetrazole group. Typicalsalts would be the sodium, potassium, calcium, ammonium, organic amino,magnesium, etc. salt. The preferred salts are relatively non-toxic, thuspharmaceutically acceptable salts, preferably the sodium salt. Compoundsof this invention may form acid addition salt with strong acids, such ashydrochloric acid.

The preferred compounds of the invention are those wherein R ishydrogen, lower alkyl or phenyl and R¹ is hydrogen or lower alkyl.

Certain of the compounds of this invention are capable of existing inthe form of hydrates or solvates. For the purposes of this invention,these other forms of the compounds are considered equivalent to thenon-hydrated or non-solvated compounds and are intended to beencompassed within the scope of the invention.

The compounds of the invention may be prepared by various routes. Thecompounds of formulae I to III and salts thereof, except in the case offormula III where R or R¹ is chloro, bromo or hydrogen, are preferablyprepared by reacting an appropriately substituted (amino) (lower alkoxycarbonyl) thiophene compound with a 6-halo-3-Z-pyridine compound whereinZ is as previously defined.

Compounds of the formula I and salts thereof may be prepared by reactinga compound of the formula: ##STR4## with a compound of the formula##STR5## wherein halo is chloro, bromo, iodo or fluoro, preferablychloro and R,R¹ and Z are as previously defined. The reactiontemperature is from about 130° C. to about 190° C. and reaction time isone-half hour to twenty-four hours, preferably 170° to 180° C. for fromtwo to eight hours. The reaction may be run neat or conducted in a highboiling acidic solvent, such as phenol. The ratios of reactants are notcritical and approximately equimolar concentrations are employed. Thisprocedure is preferred wherein Z is --CO₂ H,--CONH₂ and --CO₂ -loweralkyl.

The starting materials employed in the above process of the formula IVare either known or readily prepared by reacting a compound of theformula. ##STR6## with ethyl or methyl cyanoacetate in the presence ofsulfur and a secondary or tertiary amine.

The starting materials employed in the above process of the formula Vare commerically available, such as those wherein Z is --COOH or CO₂-lower alkyl or readily prepared from these two available materials bystandard procedures, such as reaction with aminotetrazole, ammonia,conversion to a nitrile followed by treatment with an azide, etc.

In addition, the compounds of the invention of formula I can be preparedusing the above procedure wherein Z is cyano and converting the productof the formula ##STR7## into a compound of the invention by partialhydrolysis employing aqueous strong base and heat followed byacidification to give an amido compound or complete hydrolysis employingaqueous strong acid and heat to give a carboxy compound.

Other methods wherein compounds of the invention can be converted toother compounds of the invention also involve interconversions of the Zgroup. More specifically, the carboxyl containing compounds of theformula I may be converted to the corresponding esters of the formula Ivia acid (hydrochloric, benzenesulfonic, etc.) catalysted reactions ininert solvents at temperatures of from about 10° C. to the refluxtemperature of the solvent for from fifteen minutes to twenty-fourhours. The carboxylic acid esters may be converted to the free acids ofthe invention by use of strong bases (sodium hydroxide, potassiumhydroxide, etc.) in inert solvents followed by acidification.

The nitrile of the formula I can be prepared by dehydrating thecorresponding amide.

A carboxylic acid of formula I can be converted to acarboxamidotetrazole of formula I by initially converting the carboxylicacid to a reaction intermediate by coupling it with at least oneequivalent of 1,1'-carbonyldiimidazole or other coupling agent. Thereaction takes place in a polar solvent, such as dimethylformamide forfrom one to sixteen hours at a temperature of from about 40° C. to about110° C., preferably one hour at 70° C.

The 5-aminotetrazole to be coupled to the above imidazolide ispreferably silylated using a silylating agent, such astrimethylchlorosilane and an organic or inorganic base, such astrialkylamine in a polar solvent, such as dimethylformamide for a periodof from thirty minutes to two and one-half hours at from 0° C. to 25°C., preferably one hour at 0° C. to 5° C.

The two components are combined in a polar solvent, such asdimethylformamide, for periods of from four to seventy-two hours atabout room temperature to 110° C., preferably fourteen hours at roomtemperature.

Lastly, the nitrile of formula VII may be converted to tetrazolecompounds of the formula I wherein the tetrazole is linked directly tothe pyridine ring by treatment with approximately one equivalent of anazide salt, such as sodium azide in the presence of approximately oneequivalent of an ammonium salt, such as ammonium chloride, in an inertpolar solvent, such as dimethylformamide at temperatures of from 50° C.to 125° C., preferably 100° C., for from two to forty-eight hours,preferably twenty-four hours.

Compounds of the formula II and salts thereof may be prepared byreacting a compound of the formula. ##STR8## with a compound of theformula ##STR9## wherein halo, R,R¹ and Z are as previously defined. Thereaction temperature is from about 130° C. to about 190° C., andreaction time is one-half hour to twenty-four hours, preferably 170° C.to 180° C. for from two to eight hours. The reaction may be run neat orin a high boiling acidic solvent, such as phenol. The ratios ofreactants are not critical and approximately equimolar concentrationsare employed. This procedure is preferred wherein Z is CO₂, CO₂ -loweralkyl and CONH₂.

The starting materials employed in the above process of the formula VIIIare either known or readily prepared by reacting a compound of theformula ##STR10## with a lower alkyl mercaptoacetate in the presence ofa base.

The starting materials of formula IX are prepared by chlorinating acompound of the formula ##STR11## using chlorine in the presence ofpyridine.

In addition, the compounds of the invention can be prepared using theabove procedure wherein Z is cyano and converting the compound of theformula ##STR12## into a compound of the invention by partial hydrolysisemploying aqueous strong base and heat followed by acidification to givean amido compound or complete hydrolysis employing aqueous strong acidand heat to give a carboxy compound.

Other methods wherein compounds of the invention can be converted toother compounds of the invention also involve interconversions of the Zgroup. More specifically, the carboxyl containing compounds of theformula II may be converted to the corresponding esters of the formulaII via acid (hydrochloric, benzenesulfonic, etc.) catalysed reactions ininert solvents at temperatures of from about 10° C. to the refluxtemperature of the solvent for from fifteen minutes to twenty-fourhours.

The reverse of the above procedure, that is the conversion of an esterof formula II to a carboxylic acid of formula II is achieved by carryingout a de-esterification reaction using a strong base, such as sodiumhydroxide or potassium hydroxide in an inert polar solvent. Thetemperature may be from 10° C. to the reflux temperature of the solventfor about fifteen minutes to twenty-four hours followed by adjusting thepH.

A carboxylic acid or ester of formula II can be converted to an amide offormula II by heating in a concentrated solution of ammonia. Thereaction may be conducted in an inert polar solvent, such as an alcoholor water using a large excess of ammonia at temperatures of from about50° C. to the reflux temperature of the solvent for periods of fromfifteen minutes to twenty-four hours.

The nitriles of the formula II can be prepared by dehydration of thecorresponding amide.

A carboxylic acid of formula II can be converted to acarboxamidotetrazole of formula II by initially converting thecarboxylic acid to a reactive intermediate by coupling it with at leastone equivalent 1,1'-carbonyldiimidazole or other coupling agent. Thereaction takes place in a polar solvent, such as dimethylformamide forfrom one to sixteen hours at a temperature of from about 40° C. to about110° C., preferably one hour at 70° C.

The 5-aminotetrazole to be coupled to the above imidazolide ispreferably silylated using a silylating agent, such astrimethylchlorosilane and an organic or inorganic base, such astrialkylamine, in a polar solvent, such as dimethylformamide for aperiod of from thirty minutes to two and one-half hours at from 0° C. to25° C., preferably one hour at 0° C. to 5° C.

The two components are combined in a polar solvent, such asdimethylformamide, for periods of from four to seventy-two hours atabout room temperature to 110° C., preferably fourteen hours at roomtemperature.

Lastly, the nitrile of formula IX may be converted to tetrazolecompounds of the formula II wherein the tetrazole is linked directly tothe pyridine ring by treatment with approximately one equivalent of anazide salt, such as sodium azide in the presence of approximately oneequivalent of an ammonium salt, such as ammonium chloride, in an inertpolar solvent, such as dimethylformamide at temperatures of from 50° C.to 125° C., preferably 100° C., for from two to forty-eight hours,preferably twenty-four hours.

Compounds of the formula III and salts thereof may be prepared byreacting a compound of the formula ##STR13## with a compound of theformula ##STR14## wherein halo, R,R¹ and Z are as previously defined.The reaction temperature is from about 130° C. to about 190° C. andreaction time is one-half hour to twenty-four hours, preferably 170° C.to 180° C. for from two to eight hours. The reaction may be run neat orin a high boiling acidic solvent, such as phenol. The ratios ofreactants, are not critical and approximately equimolar concentrationsare employed. This procedure is preferred wherein Z is CO₂ H, CO₂ -loweralkyl and CONH₂.

The starting materials employed in the above process of the formula XIIare readily prepared by treating a compound of the formula ##STR15##with hydrochloric acid followed by ammonium hydroxide

The compounds of the formula XIII are prepared by treating a compound ofthe formula ##STR16## with hydroxylamine.

The compounds of the formula XIV are prepared by reacting a lower alkylmercaptoacetate with a lower alkyl substituted and unsubstituted,unsaturated carboxylic acid ester in the presence of base.

In addition, the compounds of the invention can be prepared using theabove procedure wherein Z is cyano and converting the compound of theformula ##STR17## into a compound of the invention by partial hydrolysisemploying aqueous strong base and heat followed by acidification to givean amide compound or complete hydrolysis employing aqueous strong acidand heat to give a carboxy compound.

Other methods wherein compounds of the invention can be converted toother compounds of the invention also involve interconversions of the Zgroup. More specifically, the carboxyl containing compounds of theformula III may be converted to the corresponding esters of the formulaIII via acid (hydrochloric, benzenesulfonic, etc.) catalysed reactionsin inert solvents at temperatures of from about 10° C. to the refluxtemperature of the solvent for from fifteen minutes to twenty-fourhours.

The reverse of the above procedure, that is the conversion of an esterof formula III to a carboxylic acid of formula III is achieved bycarrying out a de-esterification reaction using a strong base, such assodium hydroxide or potassium hydroxide in an inert polar solvent. Thetemperature may be from 10° C. to the reflux temperature of the solventfor about fifteen minutes to twenty-four hours followed by adjustment ofthe pH.

A carboxylic acid or ester of formula III can be converted to an amideof formula III by heating in a concentrated solution of ammonia. Thereaction may be conducted in an inert polar solvent, such as an alcoholor water using a large excess of ammonia at temperatures of from about30° C. to the reflux temperature of the solvent for periods of fromfifteen minutes to twenty-four hours.

The nitriles of the formula III can be prepared from the correspondingamide by dehydration.

A carboxylic acid of formula III can be converted to acarboxamidotetrazole of formula III by initially converting thecarboxylic acid to a reactive intermediate by coupling it with at leastone equivalent of 1,1'-carbonyldiimidazole or other coupling agent. Thereaction takes place in a polar solvent, such as dimethylformamide forfrom one to sixteen hours at a temperature of from about 40° C. to about110° C., preferably one hour at 70° C.

The 5-aminotetrazole to be coupled is preferably silylated using asilylating agent, such as trimethylchlorosilane and an organic orinorganic base, such as trialkylamine. The reaction is conducted in apolar solvent, such as dimethylformamide for a period of from thirtyminutes to two and one-half hours at from 0° C. to 25° C., preferablyone hour at 0° C. to 5° C.

The two components are combined in a polar solvent, such asdimethylformamide, for periods of from four to seventy-two hours atabout room temperature to 110° C., preferably fourteen hours at roomtemperature.

Lastly, the nitrile intermediate of formula XV may be converted totetrazole compounds of the formula III wherein the tetrazole is linkeddirectly to the pyridine ring by treatment with approximately oneequivalent of an azide salt, such as sodium azide in the presence ofapproximately one equivalent of an ammonium salt, such as ammoniumchloride, in an inert polar solvent, such as dimethylformamide attemperatures of from 50° C. to 125° C., preferably 100° C., for from twoto forty-eight hours, preferably twenty-four hours.

Compounds of formula I, II and III and salts thereof can be prepareddirectly by cyclizing compounds of the formulae ##STR18## respectively,or their corresponding lower alkyl esters. The compounds wherein Z is--CO₂ H are prepared in a polar solvent, such as water, containing alarge excess of a strong acid, such as hydrochloric acid. The reactionis generally conducted at temperatures of from 20° C. to the refluxingtemperature of the solvent for from eight to twenty-four hours,preferably reflux temperature for eighteen hours. The compounds whereinZ is ##STR19## are prepared by the same procedure as given previouslyfor introducing this function onto the already closed ring. Thereaction, in one step, closes the ring and introduces the tetrazolegroup. The silylation step is optional in the foregoing procedure.

While, as shown earlier, the preferred process for preparing compoundsof the formulae I to III and salts thereof (except in formula III, R andR¹ cannot be bromo, chloro or hydrogen) involves reacting a compound ofthe formula ##STR20## with a compound of the formula V, where R and R¹are as previously defined, another process which is capable of formingcompounds of the formulae I to III and salts thereof is the preferredprocess for preparing compounds of formula III and salts thereof,especially where R and R¹ is hydrogen. This preferred process involvesthe treatment of a novel compound of the formula ##STR21## wherein X is--CH₂ -- and X¹ is CH₂, X is --CH₂ CH₂ -- and X¹ is a single bond, and Xis a single bond and X¹ is --CH₂ CH₂ -- bond; Z¹ is CO₂ lower alkyl,cyano or a protective derivative of a carboxyl, or groups such as thetri(lower alkyl)silyl derivative and R and R¹ are as previously defined,with an N-haloamide, preferably an N-halosuccinimide, wherein halo isbromo or chloro in a basic solvent, preferably pyridine. Approximatelyequivalent amounts of reactants are employed at temperatures of fromabout 50° C. to about 120° C., preferably 90° C. to 95° C. The reactiontime is not critical and is a function of the temperature; however,generally about 10 minutes to about two hours are employed with apreferred time of twenty minutes.

The starting materials of the formula XX and salts thereof, which arepart of the present invention, are prepared by reacting a compound ofthe formula ##STR22## wherein X, X¹, R, R¹ are as previously defined,with a compound of the formula ##STR23## wherein Z is as previouslydefined, in the presence of an acid catalyst, preferably toluenesulfonicacid or benzenesulfonic acid.

This reaction is generally run neat although this is not essential withabout two equivalents of compound XXI for each equivalent of compoundXXII. The reaction is carried out at about 160° C. to about 185° C.,preferably 170° C. for from about 30 minutes to about 24 hours,preferably about one to two hours.

Starting materials of the formula XXII are generally known or preparedfrom the readily available compound where Z is carboxyl by methodsdescribed earlier for interconverting the functional group on compoundsof the invention. The starting material of the formula XXI wherein X andX¹ is --CH₂ -- and R and R¹ are as previously described are prepared bytreating a compound of the formula ##STR24## with sodium methoxide in amethanolic solvent.

Compounds of the formula XXIII are prepared by reacting a compound ofthe formula ##STR25## with a compound of the formula ##STR26## in thepresence of piperidine

Starting materials of the formula XXI wherein X is --CH₂ CH₂ -- and X¹is a single bond and R and R¹ are as previously described are preparedby a literature procedure reported in Rec. Trav. Chim. Pays - Bas 96 (6)(1977)161 which is incorporated by reference.

Starting materials of the formula XXI where X is a single bond and X¹ is--CH₂ CH₂ -- and R and R¹ are as previously described are usuallyemployed in a semi-pure state with a contaminant of the formula##STR27##

This contaminant may be removed by chromatography at any desirablestage.

The above starting material having the formula ##STR28## is prepared bycyclizing a compound of the formula ##STR29## using sodium methoxide.

The compounds of the formula XXVII are prepared by reacting a compoundof the formula ##STR30## with a compound of the formula ##STR31## in thepresence of piperidine

Lastly compounds of the invention wherein R or R¹ is chloro or bromo areprepared from a compound of formula XX wherein R and R¹ are hydrogen,lower alkyl, phenyl or X-substituted phenyl where X is as previouslydefined with the proviso that when R is a group other than hydrogen, R¹is hydrogen and when R¹ is a group other than hydrogen, R is hydrogen bya direct halogenation procedure.

The process employs a trialkylchlorosilane, pyridine and an excess ofN-halosuccinimide where halo is chloro or bromo. The process is carriedout using the same conditions used to prepare compounds of the formula Ito III.

The compounds of this invention are useful pharmacological agents. Morespecifically, the compounds are useful in the treatment of allergies,such as asthma, hay fever, rhinitis, and other allergic conditions.

The compounds may be administered orally, parenterally, rectally, or byinhalation therapy. The usual mammalian dosage such as for dogs, cats,etc., range for a 70 kg subject from about 7 mg to about 1 g per day(0.1 mg to 15 mg per kg of weight per day), preferably 21 mg to 350 mgper day (0.3 mg to 5 mg per kg of weight per day), optionally in dividedportions.

The above employed pharmaceutical compositions are produced byformulating a compound of the foregoing formula (active ingredient) indosage unit form with a pharmaceutical carrier. Some examples of dosageunit forms are tablets, capsules, lozenges, and pills; as well aspowders and aqueous and non-aqueous oral solutions and suspensions andparenteral solutions, nose drops or sprays and inhalation aerosols,packaged in containers containing either one or some larger number ofdosage units and capable of being subdivided into individual doses bysuch means as measurement into a teaspoon or other standard container.Some examples of suitable pharmaceutical carriers, includingpharmaceutical diluents, are gelatin capsules; sugars such as lactoseand sucrose; starches such as corn starch and potato starch; cellulosederivatives such as sodium carboxymethyl cellulose, ethyl cellulose,methyl cellulose, and cellulose acetate phthalate; gelatin; talc,stearic acid; magnesium stearate; vegetable oils such as peanut oil,cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma;propylene glycol; glycerine, sorbitol; polyethylene glycol; water; agar;alginic acid; isotonic saline, and phosphate buffer solutions; as wellas other compatible substances normally used in pharmaceuticalformulations. The compositions of the invention can also contain othercomponents such as coloring agents, flavoring agents, and/orpreservatives. These materials, if present, are usually used inrelatively small amounts. The compositions can, if desired, also containother therapeutic agents, and where the pharmaceutical is part of aspray inhaler, it may contain non-toxic propellants.

The percentage of the active ingredient in the foregoing compositionscan be varied within wide limits but for practical purposes it ispreferably present in a concentration of at least 10% in a solidcomposition and at least 2% in a primarily liquid composition. The mostsatisfactory compositions are those in which a much higher proportion ofthe active ingredient is present. The compositions of the inventionpreferably contain from 2 mg. to 1.0 g of the active ingredient perdosage unit so that the entire amount to be administered during a daycan be made up from a reasonable number of dosage units.

The anti-allergic activity of the compounds of this invention has beendetermined using the passive cutaneous anaphylaxis (PCA) test asdescribed in Immunopharmacology, ed. M. E. Rosenthale and H. C.Mansmann, John Wiley and Son, N.Y., U.S.A., 1975, pages 103-124 and U.S.Pat. No. 4,056,532. The activity of most of the preferred compounds isgiven in the accompanying table.

In addition, compounds of formula I to III are useful as intermediatesin forming other compounds of formulae I to III as shown above.

The invention is further illustrated by the following examples.

    __________________________________________________________________________    ACTIVITY IN PCA TEST                                                                                             PCA TEST                                                                      I.V.     I.P.     P.O.                                                        % Inhib-                                                                           Dose                                                                              % Inhib-                                                                           Dose                                                                              % Inhib-                                                                           Dose                COMPOUND                           ition                                                                              mg/kg                                                                             ition                                                                              mg/kg                                                                             ition                                                                              mg/kg               __________________________________________________________________________    2-Methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic                                              Ncid 0.1 100  5   62   5                                                                        N    1                                                      33   0.1 100  5   100  5                                                      N    0.01         100  2.5                 2-Ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic                                                                 67id 1.0                                                                      69   0.5                                                                      N    0.1                 2-Ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic                                                        100  5   75   5                   acid, methyl ester                                                            4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic                                              Ncid 0.1  68  5   80   5                                                                        18   1.0                                                                      N    0.1                 2,3-Dimethyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido-[1,2-a]-thieno[2,3-d]-                                           23   0.1  94  5   N    5                   pyrimidine-7-carboxamide           18   0.01                                  2-Methyl-4-oxo-4H-pyrido[1,2-a]thiene[2,3-d]pyrimidine-7-carboxamide                                                      100  5   38   5                                                                88  5   100  5                   2-Methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile                                                              12   1                                                                        N    0.5                 2-Methyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-4-on    e                                  18   0.1 100  5   N    5                                                      N    0.01                                                                     56   0.1  97  5   100  5                                                      N    0.05         72   1                   2-Ethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one                                                          51   1                                                                        38   0.5                                                                      36   0.5                 2-Propyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidin-4-on    e                                           100  5   67   5                   2-Phenyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one    o                                            84  5   N    5                   2-(1-Methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]d]pyrimidine-7-                                                      100  5                            carboxamide                                                                   2-(1-Methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxyl    ic                                          100  5                            acid                                                                          2-Methyl-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidin-                                                     51  5                            10-one                                                                        2-Methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic         acid                                         61  5   41   5                   10-oxo-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-                                                         100  5                            7-carboxamide                                                                 1,3-Dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-                                                            70  5                            carboxylic acid                                                               7-(1H-Tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-10-one                                                      100  5                            3,10-Dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno-                                                          100  5                            [3,1-d]pyrimidine                                                             __________________________________________________________________________     N is level where no significant activity was shown                            blank space indicates no test was conducted.                             

EXAMPLE 12-Methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid

A mixture of 2-amino-5-methyl-3-thiophenecarboxylic acid, ethyl ester(Chemische Berichte, Vol. 99, page 94-100, 1966), 18.5 g (0.1 mol) and6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), 15.7 g(0.1 mol) is heated in an oil bath at 170°-190° C. for 20 hours. Themixture is cooled, extracted with hot chloroform and the residue isdissolved in hot pyridine, cooled and 0.4 g of2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acidis collected; mp 312°-315° C. after recrystallization from methanol.

EXAMPLE 22-Ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid

A mixture of 2-amino-5-ethyl-3-thiophenecarboxylic acid, ethyl ester(Chemische Berichte, Vol. 99, pages 94-100, 1966), 2.0 g (0.01 mol) and6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), 1.6 g(0.01 mol) is heated in an oil bath at 180°-185° C. for six hours. Themixture is cooled, dissolved in hot glacial acetic acid, activatedcharcoal (Darco G-60, Matheson, Coleman and Bell) added and the hotsuspension filtered through Supercell Hyflo® (Johns-Manville). Thefiltrate is cooled and 0.33 g of2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxylic acidis collected; mp 255°-257° C. after recrystallization from methanol.

EXAMPLE 34-Oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid

A mixture of 2-amino-5-propyl-3-thiophenecarboxylic acid, ethyl ester,7.4 g (0.035 mol) and 6-chloro-3-pyridinecarboxylic acid (AldrichChemical Company), 6.4 g (0.041 mol) is heated in an oil bath at 180° C.for two hours. The mixture is cooled, extracted with hot chloroform andthe residue is dissolved in hot pyridine, cooled and 0.45 g of4-oxo-2-propyl-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxylicacid is collected; mp 250°-254° C. after recrystallization frompyridine.

EXAMPLE 42-Butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid

A mixture of 2-amino-5-butyl-3-thiophenecarboxylic acid, methyl ester,21.33 g (0.1 mol) and 6-chloro-3-pyridinecarboxylic acid (AldrichChemical Company), 15.76 g (0.1 mol) is heated in a wax bath at178°-180° C. for one hundred ninety minutes. The mixture is cooled,extracted with hot chloroform and the residue is dissolved in 300 ml ofhot glacial acetic acid filtered and 600 ml of hot water added and themixture stirred on a steam bath for forty minutes and filtered to give1.23 g of2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid;mp 250°-252° C. after recrystallization from pyridine.

EXAMPLE 5 4-Oxo-B2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid

From 5.0 g (0.02 mol) of 2-amino-5-phenyl-3-thiophenecarboxylic acid,ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) and 3.2 g(0.02 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich ChemicalCompany), following the procedure of Example 3, there is obtained 0.4 gof 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno [2,3-d]pyrimidine-7-carboxylicacid; mp 387°-392° C. after recrystallization from pyridine.

EXAMPLE 62,3-Dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylicacid

From 8.0 g (0.04 mol) of 2-amino-4,5-dimethyl-3-thiophenecarboxylicacid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) and6.3 g (0.04 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich ChemicalCompany) following the procedure of Example 3, there is obtained 0.2 gof2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylicacid; mp 364°-368° C. after recrystallization from pyridine.

EXAMPLE 72-Ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid,methyl ester

A mixture of 10 g (0.05 mol) of 2-amino-5-ethyl-3-thiophenecarboxylicacid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) and8.61 g (0.05 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester(Alfred Bader Chemical Company) is heated in a wax bath at 178°-188° C.for three hours under nitrogen. The distillate is collected in aDean-Stark trap attached to the reaction flask. The mixture is cooled,dissolved in hot methanol, cooled and 5.5 g of2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid,methyl ester is collected; mp 151°-152° C. after recrystallization frommethanol.

EXAMPLE 82-Butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid,methyl ester

From 5.1 g (0.024 mol) of 2-amino-5-butyl-3-thiophenecarboxylic acid,methyl ester and 4.1 g (0.024 mol) of 6-chloro-3-pyridinecarboxylicacid, methyl ester (Alfred Bader Chemical Company), following theprocedure of Example 7, there is obtained 3.2 g of2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid,methyl ester; mp 137°-138° C. after recrystallization from methanol.

EXAMPLE 92-Methyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxamide

1.86 g (0.00715 mol) of2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid(Example 1) and 1.62 g (0.01 mol) of 1,1'carbonyldiimidazole (AldrichChemical Company) in 210 ml of dimethylformamide are stirred at 50° C.for sixteen hours. To 0.83 g (0.008 mol) of 5-aminotetrazole monohydrate(Aldrich Chemical Company) in 50 ml of dimethylformamide cooled to 0°-5°C. is added 3.0 ml (0.024 mol) of chlorotrimethylsilane (AldrichChemical Company) and 6.0 ml (0.043 mol) of triethylamine. After thirtyminutes the mixture is allowed to reach room temperature and is stirredfor an additional two hours. This mixture is combined with the previouscooled imidazolide mixture and stirred for three days at roomtemperature. The resulting precipitate is collected, slurried in boilingglacial acetic acid, the mixture is cooled and filtered to give 0.69 gof 2-methyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 306°-310° C. (dec).

EXAMPLE 10 2-Ethyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxamide

0.64 g (0.0023 mol) of2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxylic acid(Example 2) and 0.75 g (0.0046 mol) of 1,1'carbonyldiimidazole (AldrichChemical Company) in 70 ml of dimethylformamide are stirred at 70° C.for two and one-half hours. To 0.31 g (0.003 mol) of 5-aminotetrazolemonohydrate (Aldrich Chemical Company) in 40 ml of dimethylformamidecooled to 0°-5° C. is added 1.5 ml (0.012 mol) of chlorotrimethylsilane(Aldrich Chemical Company) and 2.5 ml (0.018 mol) of triethylamine. Themixture is stirred and allowed to reach room temperature. After twohours the mixture is combined with the previous imidazolide mixture andstirred for fourteen hours at room temperature. The resultingprecipitate is collected, slurried in boiling glacial acetic acid, themixture is cooled and filtered to give 0.58 g of2-ethyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 310°-312° C. (dec).

EXAMPLE 114-Oxo-2-propyl-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxamide

5.77 g (0.02 mol) of4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxylicacid (Example 3) and 6.49 g (0.04 mol) of 1,1'carbonyldiimidazole(Aldrich Chemical Company) in 100 ml of dimethylformamide are stirred at50° C. for one hour. To 2.5 g (0.024 mol) of 5-aminotetrazolemonohydrate (Aldrich Chemical Company) in 50 ml of dimethylformamidecooled to 0°-5° C. is added 9.14 ml (0.072 mol) of chlorotrimethylsilane(Aldrich Chemical Company) and 10 ml (0.072 mol) of triethylamine. Themixture is stirred and allowed to reach room temperature. After twohours the mixture is combined with the previous imidazolide mixture andstirred for fourteen hours at room temperature. The resultingprecipitate 0.9 g, of4-oxo-2-propyl-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamideis collected; mp 306°-308° C. (dec) after recrystallization frompyridine.

EXAMPLE 122-Butyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxamide

1.6 g (0.0053 mol) of2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxylic acid(Example 4) and 1.75 g (0.0108 mol) of 1,1' carbonyldiimidazole (AldrichChemical Company) in 50 ml of dimethylformamide are stirred under anitrogen atmosphere at 105° C. for seventy minutes. The mixture isallowed to stand at room temperature for thirty minutes and then 0.545 g(0.00529 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company)is added and the mixture heated at 105° C. for one hundred minutes. Thesolvent is evaporated and the residue is dissolved in dimethylformamideand filtered. The filtrate is cooled and 1.1 g of2-butyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxamideis collected; mp 290° (dec).

EXAMPLE 134-Oxo-2-phenyl-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxamide

0.9 g (0.0028 mol) of4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxylicacid (Example 5) and 0.7 g (0.0043 mol) of 1,1'carbonyldiimidazole(Aldrich Chemical Company) in 80 ml of dimethylformamide are stirred at60°-70° C. for five hours. To 0.4 g (0.004 mol) of 5-aminotetrazolemonohydrate (Aldrich Chemical Compay) is 40 ml of dimethylformamidecooled to 0°-5° C. is added 1.5 ml (0.012 mol) of chlorotrimethylsilane(Aldrich Chemical Company) and 3 ml (0.022 mol) of triethylamine. Afterthirty minutes the mixture is allowed to reach room temperature and isstirred for an additional two hours. The mixture is combined with theprevious imidazolide mixture and stirred for fourteen hours at roomtemperature. The resulting precipitate is collected, slurried in boilingglacial acetic acid, and mixture is cooled and filtered to give 0.78 gof 4-oxo-2-phenyl-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 324°-328° C. (dec).

EXAMPLE 142,3-Dimethyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno-[2,3-d]-pyrimidine-7-carboxamide

From 1 g (0.0036 mol) of2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxylicacid (Example 6), 0.83 g (0.0051 mol) of 1,1'carbonyldiimidazole(Aldrich Chemical Company) in 50 ml of dimethylformamide and 0.41 g(0.004 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company),1.5 ml (0.012 mol) of chlorotrimethylsilane (Aldrich Chemical Company),3.0 ml (0.022 mol) of triethylamine in 40 ml of dimethylformamide,following the procedure of Example 11, there is obtained 0.73 g of2,3-dimethyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxamideafter slurrying in boiling glacial acetic acid, cooling and filteringthe precipitate; mp 297°-300° C. (dec).

EXAMPLE 152-(1-Methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide

A mixture of 24.0 g (0.1538 mol) of 6-chloro-3-pyridine-carboxamide(Aldrich Chemical Company) and 32.8 g (0.1538 mol) of2-amino-5-(1-methylethyl)-3-thiophenecarboxylic acid, ethyl ester(Tetrahedron, Vol. 33, pages 2089-2092, 1977) is heated in a wax bath at178°-182° C. for two hundred five minutes and then at 180°-196° C. forsixty-five minutes under nitrogen. The mixture is cooled, suspended inhot methanol and filtered to give 8.9 g of2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine7-carboxamide; mp 280°-282° C. after recrystallization fromdimetylformamide.

EXAMPLE 162-(1-Methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile

2-(1-Methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide(Example 15), 8.7 g (0.0303 mol), in 250 ml of phosphorus oxychlorideand 250 ml of chloroform is refluxed on a steam bath for four hoursunder nitrogen. The chloroform and excess phosphorus oxychloride areevaporated in vacuo and the residue is treated with 2 L of ice water.The resulting precipitate is filtered to give 5.3 g of2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile;mp 225°-226° C. after recrystallization from pyridine.

EXAMPLE 172-(1-Methylethyl)-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidin-4-one

A mixture of 5.1 g (0.01894 mol) of2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile(Example 16), 6.5 g (0.1 mol ) of sodium azide and 5.35 g (0.1 mol) ofammonium chloride in 150 ml of dimethylformamide is stirred and heatedat 124° C. for twenty-two hours under nitrogen. The reaction mixture iscooled, filtered and the filtrate evaporated. The residue is treatedwith 1 1 water and acidified with concentrated hydrochloric acid. Theresulting precipitate is collected, suspended in hot water, thesuspension cooled and filtered to give 3.3 g of2-(1-methylethyl)-7-(1H-tetrazol-5-yl)-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidin-4-one;mp 288° C. (dec) after recrystallization from pyridine-ethanol.

EXAMPLE 182-(1-Methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylicacid

A mixture of 21.33 g (0.1 mol) of2-amino-5-(1-methylethyl)-3-thiophenecarboxylic acid, ethyl ester(Tetrahedron, Vol. 33, pages 2089-2092, 1977) and 17.16 g (0.1 mol) of6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader ChemicalCompany) is heated in a wax bath at 178°-182° C. for one hundredeighty-seven minutes and then at 182°-205° C. for ninety minutes undernitrogen. The distillate is collected in a Dean-Stark Trap attached tothe reaction flask. The mixture is cooled, dissolved in methanol, cooledand 16.2 g of a mixture of2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylicacid, methyl ester and the ring-opened diester,6-[[3-(ethoxycarbonyl)-5-(1-methylethyl)-2-thienyl]amino]-3-pyridinecarboxylicacid, methyl ester, is collected; mp 112°-114° C. A suspension of 11 gof the previous mixture in 250 ml of concentrated hydrochloric acid and250 ml of water is refluxed in a wax bath at 142° C. for twenty-twohours under nitrogen. The suspension is cooled to room temperature,filtered and the precipitate washed with 300 ml of water and dried togive 6.0 g of2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylicacid; mp 264°-266° C. after recrystallization from ethanol.

EXAMPLE 192-(1-Methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylicacid, ethyl ester

A cooled suspension of 1.4 g (0.00486 mol) of2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-7-carboxylicacid (Example 18) in 150 ml of ethanol is saturated with hydrogenchloride. The mixture is stirred and refluxed in a wax bath at 128° C.for eighteen hours under nitrogen. The ethanol is evaporated in vacuo togive 0.43 g of2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylicacid, ethyl ester; mp 122°-123° C. after recrystallization from absoluteethanol.

EXAMPLE 202-(1-Methylethyl)-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxamide

2.88 g (0.01 mol) of2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidin-7-carboxylicacid (Example 18) and 3.31 g (0.02 mol) of 1,1' carbonyldiimidazole(Aldrich Chemical Company) in 100 ml of dimethylformamide are stirredand heated in a wax bath at 105° C. for ninety minutes under nitrogen.The mixture is cooled and stirred at room temperature for thirty minutesand 1.03 g (0.01 mol) of 5-aminotetrazole monohydrate (Aldrich ChemicalCompany) is added and the resulting mixture is stirred and heated at105° C. for one hundred thirty-five minutes under nitrogen. The mixtureis allowed to stand overnight at room temperature, the precipitate isfiltered and the filtrate is evaporated in vacuo. The residue isslurried in boiling methanol, the mixture cooled and filtered. Thisprecipitate is combined with the previous precipitate to give 1.8 g of2-(1-methylethyl)-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxamide; mp 307° C. (dec) after recrystallization from pyridine.

EXAMPLE 212-Methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide

A mixture of 6.0 g (0.038 mol) of 6-chloro-3-pyridinecarboxamide(Aldrich Chemical Company) and 10.0 g (0.054 mol) of2-amino-3-methyl-3-thiophenecarboxylic acid, ethyl ester (ChemischeBerichte, Vol. 99, pages 94-100, 1966) is heated in an oil bath at 185°C. for one hour then at 135°-140° C. for sixteen hours and finally at195° C. for six hours. The mixture is cooled and then suspended in hotchloroform and filtered to give 0.6 g of2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp350°-354° C. after recrystallization from pyridine.

EXAMPLE 222-Ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide

A mixture of 6.0 g (0.038 mol) of 6-chloro-3-pyridinecarboxamide(Aldrich Chemical Company) and 8.0 g (0.040 mol) of2-amino-5-ethyl-3-thiophenecarboxylic acid, ethyl ester (ChemischeBerichte, Vol. 99, pages 94-100, 1966) is heated in an oil bath at 180°C. for two hours. The mixture is cooled and then suspended in hotchloroform and filtered to give 1.8 g of2-ethyl-4-oxo-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp278°-280° C. after recrystallization from pyridine.

EXAMPLE 234-Oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide

From 4.6 g (0.0029 mol) of 6-chloro-3-pyridinecarboxamide (AldrichChemical Company) and 8.6 g (0.040 mol) of2-amino-5-propyl-3-thiophenecarboxylic acid, ethyl ester, following theprocedure of Example 22 there is obtained 2.6 g of4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp260°-264° C. after recrystallization from pyridine.

EXAMPLE 242-Butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide

From 6.2 g (0.040 mol) of 6-chloro-3-pyridinecarboxamide (AldrichChemical Company) and 9.0 g (0.040 mol) of2-amino-5-butyl-3-thiophenecarboxylic acid, ethyl ester and heating in awax bath at 180°-195° C. for one hundred forty-five minutes and then at185°-200° C. for ninety minutes, following the procedure of Example 22there is obtained 1.9 g of2-butyl-4-oxo-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp266°-267° C. after recrystallization from glacial acetic acid.

EXAMPLE 254-Oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide,monoacetate

From 4.7 g (0.030 mol) of 6-chloro-3-pyridinecarboxamide (AldrichChemical Company) and 7.5 g (0.030 mol) of2-amino-5-phenyl-3-thiophenecarboxylic acid, ethyl ester (ChemischeBerichte, Vol. 99, pages 94-100, 1966), following the procedure ofExample 22, there is obtained 0.4 g of4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide,monoacetate; mp 348°-352° C. after recrystallization from glacial aceticacid.

EXAMPLE 262,3-Dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide

From 6.0 g (0.038 mol) of 6-chloro-3-pyridinecarboxamide (AldrichChemical Company) and 8.0 g (0.040 mol) of2-amino-4,5-dimethyl-3-thiophenecarboxylic acid, ethyl ester (ChemischeBerichte, Vol. 99, pages 94-100, 1966), following the procedure ofExample 22, there is obtained2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxamide;mp 361°-363° C. after recrystallization from pyridine.

EXAMPLE 272-Methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile

2-Methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide(Example 21), 2.6 g (0.010 mol), in 30 ml of phosphorus oxychloride and30 ml of chloroform is refluxed on a steam bath for three hours. Thechloroform and excess phosphorus oxychloride are evaporated in vacuo andthe residue is treated with 200 ml of ice water. The resultingprecipitate is filtered to give 2.1 g of2-methyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carbonitrile;mp 256°-258° C. after recrystallization from glacial acetic acid.

EXAMPLE 282-Ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile

From 1.3 g (0.0048 mol) of2-ethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxamide(Example 22), 30 ml of phosphorus oxychloride and 30 ml of chloroformand refluxing on a steam bath for six hours, following the procedure ofExample 27, there is obtained 1.18 g of2-ethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carbonitrile;mp 223°-224° C. after recrystallization from glacial acetic acid.

EXAMPLE 294-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile

From 2.0 g (0.007 mol) of4-oxo-2-propyl-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxamide(Example 23), 30 ml of phosphorus oxychloride and 30 ml of chloroform,following the procedure of Example 27, there is obtained 1.8 g of4-oxo-2-propyl-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile;mp 217°-218° C. after recrystallization from glacial acetic acid.

EXAMPLE 302-Butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile

From 4.0 g (0.0133 mol) of2-butyl-4-oxo-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxamide(Example 24), 100 ml of phosphorus oxychloride and 100 ml of chloroformand refluxing on a steam bath for four hours, following the procedure ofExample 27, there is obtained 2.1 g of2-butyl-4-oxo-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile;mp 216°-217° C. after recrystallization from pyridine.

EXAMPLE 314-Oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile

From 3.2 g (0.01 mol) of4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxamide(Example 25), 90 ml of phosphorus oxychloride and 50 ml of chloroformand refluxing for twenty-four hours, following the procedure of Example27, there is obtained 2.5 g of4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carbonitrile;mp 349°-351° C. after recrystallization from pyridine.

EXAMPLE 322,3-Dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile

From 1.0 g (0.0037 mol) of2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxamide(Example 26), 50 ml of phosphorus oxychloride and 50 ml of chloroformand refluxing on a steam bath for eighteen hours, following theprocedure of Example 27, there is obtained 0.89 g of2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile;mp 306°-307° C. after recrystallization from glacial acetic acid.

EXAMPLE 332-Methyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidin-4-one

A mixture of 1.5 g (0.0062 mol) of2-methyl-4-oxo-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile(Example 27), 1.36 g (0.021 mol) of sodium azide and 1.24 g (0.023 mol)of ammonium chloride in 280 ml of dimethylformamide is heated at110°-120° C. for twelve hours. The reaction mixture is cooled, pouredinto 1 l of ice water and acidified with concentrated hydrochloric acid.The resulting precipitate is filtered and dissolved in hot glacialacetic acid, activated charcoal (Darco-G60, Matheson, Coleman and Bell)is added and the hot suspension is filtered through Supercell Hyflo®(Johns-Manville). The filtrate is cooled to give 0.1 g of2-methyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one;mp 330°-340° C. (dec) after recrystallization from pyridine.

EXAMPLE 342-Ethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidin-4-one

A mixture of 0.65 g (0.0026 mol) of2-ethyl-4-oxo-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile(Example 28), 0.56 g (0.0086 mol) of sodium azide and 0.51 g (0.0095mol) of ammonium chloride in 80 ml of dimethylformamide is heated at100° C. for twenty-four hours. The reaction mixture is cooled, pouredinto 900 ml of ice water and acidified with concentrated hydrochloricacid. The resulting precipitate of2-ethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one,0.2 g, is collected; mp 293°-295° C. (dec) after recrystallization frompyridine.

EXAMPLE 352-Propyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one

From 0.85 g (0.0032 mol) of4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile,(Example 29), 0.68 g (0.011 mol) of sodium azide and 0.62 g (0.012 mol)of ammonium chloride in 80 ml of dimethylformamide, following theprocedure of Example 34, there is obtained 0.46 g of2-propyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one;mp 288°-292° C. (dec) after recrystallization from pyridine.

EXAMPLE 362-Butyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one

From 7 g (0.025 mol) of2-butyl-4-oxo-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carbonitrile(Example 30), 8.45 g (0.13 mol) of sodium azide and 6.85 g (0.13 mol) ofammonium chloride in 250 ml of dimethylformamide heated at 125°-128° C.under a nitrogen atmosphere, following the procedure of Example 34,there is obtained 4.6 g of2-butyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one;mp 281° C. (dec) after recrystallization fromdimethylformamide-methanol.

EXAMPLE 372-Phenyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one

A mixture of 1.5 g (0.005 mol) of4-oxo-2-phenyl-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile(Example 31), 1.0 g (0.0153 mol) of sodium azide and 0.9 g (0.0168 mol)of ammonium chloride in 200 ml of dimethylformamide is heated at110°-120° C. for three days. The reaction mixture is cooled, poured into1 l of ice water and acidified with concentrated hydrochloric acid. Theresulting precipitate is filtered and dissolved in hot pyridine,activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added andthe hot suspension is filtered through Supercell Hyflo®(Johns-Manville). The filtrate is cooled to give 0.55 g of2-phenyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one;mp 310°-312° C. (dec) after recrystallization from pyridine.

EXAMPLE 382,3-Dimethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one

From 0.43 g (0.0017 mol) of2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile(Example 32), 0.33 g (0.0051 mol) of sodium azide and 0.3 g (0.0056 mol)of ammonium chloride in 80 ml of dimethylformamide, following theprocedure of Example 34, there is obtained 0.14 g of2,3-dimethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-onewith pyridine (1:0.6); mp 292°-294° C. (dec) after recrystallizationfrom pyridine.

EXAMPLE 39 6-[(5-Butyl-3-carboxy-2-thienyl)amino]-3-pyridinecarboxylicacid

A mixture of2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid,methyl ester (Example 8), 0.94 g (0.00297 mol), 35 ml of 1 N sodiumhydroxide and 25 ml of ethanol is refluxed for fifty-five minutes. Theresulting solution is evaporated to dryness, and the residue isdissolved in hot water, filtered, cooled and acidified with glacialacetic acid. The precipitate is separated, washed with water and driedto give 0.7 g of6-[(5-butyl-3-carboxy-2-thienyl)amino]-3-pyridinecarboxylic acid; mp217° C. (dec) after recrystallization from glacial acetic acid.

EXAMPLE 402-Butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid

A mixture of 6-[(5-butyl-3-carboxy-2-thienyl)amino]-3-pyridinecarboxylicacid (Example 39), 1.0 g (0.00312 mol), 25 ml of concentratedhydrochloric acid and 25 ml of water is refluxed in a wax bath under anitrogen atmosphere at a bath temperature of 142° C. for seventeen andthree-quarter hours. The suspension is cooled to room temperature andthe precipitate is separated, washed with water and then washed withdiethyl ether and dried to give 0.595 g of2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid;mp 252°-254° C. after recrystallization from ethanol.

EXAMPLE 412-Butyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide

A mixture of 6-[(5-butyl-3-carboxy-2-thienyl)amino]-3-pyridinecarboxylicacid (Example 39), 3.2 g (0.01 mol) and 9.93 g (0.06 mol) of 1,1¹-carbonyldiimidazole (Aldrich Chemical Company) in 100 ml ofdimethylformamide is heated in a wax bath under a nitrogen atmospherewith stirring at 100° to 108° C. for seventy minutes, cooled and stirredat room temperature for one hour. To the previous mixture is added5-aminotetrazole monohydrate (Aldrich Chemical Company), 2.06 g (0.02mol) and the mixture is heated at 100°-108° C. for ninety minutes. Thesolvent is evaporated and the residue dissolved in dimethylformamide,filtered, cooled and the precipitate collected and washed with methanolto give 1.2 g of2-butyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide;mp 293° C. (dec) after recrystallization from pyridine.

EXAMPLE 422-Methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylicacid

A mixture of 1.7 g (0.01 mol) of 3-amino-5-methyl-2-thiophene-carboxylicacid, methyl ester (German Patent No. 1055007, Apr. 16, 1959) and 1.6 g(0.01 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich ChemicalCompany) is heated in an oil bath at 180° C. for two hours. The mixtureis cooled, dissolved in hot methanol, cooled and 0.23 g of2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylicacid is collected; mp 338°-340° C. after recrystallization frommethanol.

EXAMPLE 432-Methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylicacid, methyl ester

A mixture of 5 g (0.0292 mol) of 3-amino-5-methyl-2-thiophene-carboxylicacid, methyl ester (German Patent No. 1055007, Apr. 16, 1959) and 5 g(0.0292 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (AlfredBader Chemical Company) is heated in an oil bath at 180° C. for thirtyminutes. The mixture is cooled, dissolved in hot methanol, cooled and1.2 g of2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylicacid, methyl ester is collected; mp 215°-216° C. after recrystallizationfrom methanol.

EXAMPLE 442-Methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide

A mixture of 2.7 g (0.0158 mol) of3-amino-5-methyl-2-thiophene-carboxylic acid, methyl ester (GermanPatent No. 1055007, Apr. 16, 1959) and 2.5 g (0.0158 mol) of6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) is heated inan oil bath at 180°-190° C. for one hour. The mixture is cooled and thensuspended in hot chloroform and filtered to give 0.6 g of2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide;mp 375°-377° C. after recrystallization from pyridine.

EXAMPLE 452-Methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitrile

2-Methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide(Example 44), 0.6 g (0.0023 mol), in 10 ml of pyridine, 25 ml ofphosphorus oxychloride and 25 ml of chloroform is refluxed on a steambath for three hours. The solvents are evaporated in vacuo and theresidue is treated with 100 ml of ice water. The resulting precipitateis filtered to give 0.5 g of2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitrile;mp 258°-259° C. after recrystallization from methanol.

EXAMPLE 462-Methyl-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidin-10-on

A mixture of 0.21 g (0.00087 mol) of2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitrile(Example 45), 0.2 g (0.0031 mol) of sodium azide and 0.166 g (0.0031mol) of ammonium chloride in 50 ml of dimethylformamide is stirred andheated to 100° C. for twenty-four hours. The reaction mixture is cooled,poured into 900 ml of ice water and acidified with concentratedhydrochloric acid. The resulting precipitate is filtered to give 0.2 gof2-methyl-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidin-10-one;mp 321°-325° C. (dec) after recrystallization from pyridine.

EXAMPLE 472-Methyl-10-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide

0.33 g (0.0013 mol) of2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylicacid (Example 42) and 0.29 g (0.0018 mol) of 1,1¹ -carbonyldiimidazole(Aldrich Chemical Company) in 50 ml of dimethylformamide are stirred at50° C. for one hour. To 0.15 g (0.00143 mol) of 5-aminotetrazolemonohydrate (Aldrich Chemical Company) in 50 ml of dimethylformamidecooled to 0°-5° C. is added 0.7 ml (0.0054 mol) of chlorotrimethylsilane(Aldrich Chemical Company) and 0.75 ml (0.0054 mol) of triethylamine.After thirty minutes the mixture is allowed to reach room temperatureand is stirred for an additional two hours. This mixture is combinedwith the previous cooled imidazolide mixture and stirred for fourteenhours at room temperature. The resulting precipitate is collected,slurried in boiling glacial acetic acid, the mixture is cooled andfiltered to give 0.15 g of2-methyl-10-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide; mp 342°-344° C. (dec) afterrecrystallization from pyridine.

EXAMPLE 481,3-Dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid

A mixture of 18.5 g (0.1 mol) of4-amino-2,5-dimethyl-3-thiophene-carboxylic acid, methyl ester and 15.76g (0.1 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich ChemicalCompany) is heated in a wax bath at 168°-186° C. for one hundred tenminutes and then at 185°-186° C. for ninety minutes under nitrogen. Themixture is cooled, suspended in hot methanol, cooled and 4.2 g of crudeproduct is collected. This material is dissolved in hot pyridine,activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added andthe hot suspension is filtered through Supercell Hyflo®(Johns-Manville). The filtrate is cooled to give 1.75 g of1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid; mp 336° C. (dec) after recrystallization from pyridine.

EXAMPLE 491,3-Dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid, methyl ester

A mixture of 2.5 g (0.0113 mol) of4-amino-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester and 2.5 g(0.0113 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (AlfredBader Chemical Company) is heated in an oil bath at 180° C. for thirtyminutes. The mixture is cooled, dissolved in hot methanol, cooled and0.3 g of1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid, methyl ester is collected; mp 209°-210° C. after recrystallizationfrom methanol.

EXAMPLE 501,3-Dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide

A mixture of 5 g (0.0226 mol) of4-amino-2,5-dimethyl-3-thiophene-carboxylic acid, methyl ester and 3.5 g(0.0226 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich ChemicalCompany) is heated in an oil bath at 180° C. for thirty minutes. Themixture is cooled, dissolved in hot pyridine, cooled, the precipitatecollected and dissolved in hot methanol, activated charcoal (Darco-G60,Matheson, Coleman and Bell) is added and the hot suspension is filteredthrough Supercell Hyflo® (Johns-Manville). The filtrate is cooled togive 0.2 g of1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamidewith methanol (1:0.125); mp 272°-275° C. after recrystallization frommethanol.

EXAMPLE 511,3-Dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile

1,3-Dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide(Example 50), 0.6 g (0.0022 mol), in 10 ml of pyridine, 25 ml ofphosphorus oxychloride and 25 ml of chloroform is refluxed on a steambath for two hours. The solvents are evaporated in vacuo and the residueis treated with 100 ml of water. The resulting precipitate is filteredto give 0.3 g of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile withmethanol (1:0.125); mp 242°-244° C. after recrystallization frommethanol.

EXAMPLE 521,3-Dimethyl-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,4-d]-pyrimidin-10-one

A mixture of 4.4 g (0.0172 mol) of1,3-dimethyl-10-oxo-10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile(Example 51), 6.5 g (0.1 mol) of sodium azide and 5.3 g (0.1 mol) ofammonium chloride in 180 ml of dimethylformamide is stirred and heatedin a wax bath at 120° C. for seventeen hours under nitrogen. Thereaction mixture is cooled, filtered and the filtrate evaporated. Theresidue is treated with 250 ml of water and acidified with concentratedhydrochloric acid. This mixture is warmed on a steam bath, cooled andfiltered to give 5.1 g of crude product. This material is dissolved inhot pyridine, activated charcoal (Darco-G60, Matheson, Coleman and Bell)is added and the hot suspension is filtered through Supercell Hyflo®(Johns-Mansville). The filtrate is cooled to give 3.1 g of1,3-dimethyl-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno-[3,4-d]pyrimidin-10-one;mp 292° C. (dec).

EXAMPLE 531,3-Dimethyl-10-oxo-N-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxamide

A mixture of 0.6 g (0.0022 mol) of1,3-dimethyl-10-oxo-10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid (Example 48) and 0.84 g (0.005 mol) of 1,1' carbonyldiimidazole(Aldrich Chemical Company) in 90 ml of dimethylformamide is stirred andheated in a wax bath at 105° C. for eighty five minutes under nitrogen.The mixture is allowed to stand at room temperature for thiry minutesand then 0.225 g (0.0022 mol) of 5-aminotetrazole monohydrate (AldrichChemical Company) is added and the mixture heated at 105° C. for threeand one-half hours. The solvent is evaporated and the residue suspendedin hot methanol, cooled and 0.71 g of crude product is collected. Thismaterial is dissolved in hot pyridine, activated charcoal (Darco G60,Matheson, Coleman and Bell) is added and the hot suspension is filteredthrough Supercell Hyflo® (Johns-Manville). The filtrate is cooled togive 0.47 g of 1,3-dimethyl-10-oxo-N-1H-tetrazol-5-yl-10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide with pyridine(1:0.2); mp >300° C. (dec).

EXAMPLE 54 Ethyl10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylate

A mixture of ethyl3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylate(2.0 g., 0.0072 mol) and m-chloroperbenzoic acid (1.47 g., 0.0072 mol)in chloroform (75 ml) is stirred at room temperature overnight. Thesolvent is evaporated at reduced pressure to give a syrup, whichcrystallizes from ethanol. Recrystallization from ethanol, silica gelchromatography and a further recrystallization from ethanol gives theproduct as yellow crystals (mp 175° C.).

EXAMPLE 55 Ethyl10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylate

A mixture of ethyl3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylate(2.0 g., 0.0072 mol) and N-chlorosuccinimide (0.97 g., 0.0072 mol) inpyridine (20 ml) is heated on a steam bath for 18 minutes. The reactionmixture is cooled and poured into a large volume of ice water. Theprecipitate is filtered, washed with water and dried. Recrystallizationfrom ethanol gives the product (1.1 g.), mp 175°-176° C.

EXAMPLE 563-Chloro-10-oxo-10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid

Chlorotrimethylsilane (0.4 ml, 0.03 mol) is added to a cooled (ice bath)solution of3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylicacid (0.75 g., 0.03 mol) in pyridine (5 ml) under nitrogen. The mixtureis stirred at ice bath temperatures for one hour and then allowed towarm to room temperature. N-Chlorosuccinimide (0.8 g., 0.06 mol) is adddand the mixture is heated at 95° C. for 20 minutes. The mixture iscooled, diluted with water (3 ml) and stirred for 15 minutes. Theprecipitate is filtered off, dried and recrystallized from ethanol togive the product (0.5 g.), mp 285° C. (dec).

EXAMPLE 57 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid

Chlorotrimethylsilane (2.6 ml, 0.02 mol) is added to a cooled (icebath)solution of3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylicacid (5.0 g., 0.02 mol) in pyridine (40 ml) under nitrogen. The mixtureis stirred at ice bath temperature for one hour and then allowed to warmto room temperature. N-Chlorosuccinimide (2.74 g., 0.02 mol) is addedand the mixture is heated at 90°-95° C. for 20 minutes. The mixture iscooled, diluted with water (5 ml) and stirred for 15 minutes. Theprecipitate is filtered off, dried, washed with boiling acetone (3×100ml) and recrystallized from dimethylformamide to give the product (3.9g.), mp 320° C. (dec).

EXAMPLE 5810-oxo-N-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno[3,4-d]-pyrimidine-7-carboxamide

A mixture of10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (0.7g., 0.003 mol) and 1,1'-carbonyldiimidazole (0.94 g., 0.006 mol) indimethylformamide (25 ml) is heated at 100° C. with stirring undernitrogen for 1.5 hours. 5-Aminotetrazole monohydrate (0.3 g., 0.003 mol)is added and the resulting mixture is heated at 100° C. for 2 hours. Thereaction mixture is cooled and diluted with acetone. The precipitate isfiltered off, washed with boiling dimethylformamide, and dried to givethe product (0.46 g.), mp 280° C. (dec).

EXAMPLE 59 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide

A mixture of10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (6.0g., 0.024 mol) and 1,1'-carbonyldiimidazole (4.0 g., 0.024 mol) indimethylformamide (120 ml) is heated at 110° C. for 2.5 hours undernitrogen. The solution is cooled in an ice bath and anhydrous ammonia isbubbled through for 15 minutes. The mixture is stirred at ice bathtemperature for 2 hours and at room temperature for one hour. Theprecipitate is filtered off, washed with tetrahydrofuran and dried togive the product (5.2 g.), mp 340° C. (dec).

EXAMPLE 6010-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile

A mixture of10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide (3.8 g.,0.015 mol), p-toluenesulfonyl chloride (4.4 g., 0.023 mol) and pyridine(3.8 ml, 0.046 mol) in dimethylformamide (50 ml) is heated at 95° C. for1 hour. The mixture is cooled, diluted with water (5 ml) and stirred.The precipitate is filtered, washed with water and dried.Recrystallization from 2-propanol gives golden crystals (2.5 g.) mp233°-234° C.

EXAMPLE 61 Ethyl10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylate

A mixture of ethyl3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,2-d]pyrimidine-7-carboxylate(0.4 g., 0.0014 mol) and N-chlorosuccinimide (0.9 g., 0.0014 mol) inpyridine (4 ml) is heated on a steam bath for 18 minutes. The reactionmixture is cooled and poured into a large volume of ice water. Theprecipitate is filtered, washed with water and dried. Recrystallizationfrom ethanol gives the product (0.2 g.) mp 188°-190° C.

EXAMPLE 62 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid

Chlorotrimethylsilane (2.35 ml, 0.018 mol) is added to a cooled (icebath) solution of3,10-dihydro-10-oxo-1H-pyrido[1,2-a]-thieno[3,2-d]pyrimidine-7-carboxylicacid (4.5 g, 0.018 mol) in pyridine (35 ml) under nitrogen. The mixtureis stirred at ice bath temperature for 1 hour and then allowed to warmat room temperature. N-chlorosuccinimide (2.44 g, 0.018 mol) is addedand the mixture is heated at 95° C. for 20 minutes. The mixture iscooled, diluted with ice water (5 ml) and stirred for 15 minutes. Theprecipitate is filtered, washed with boiling acetone and dried to givethe product (3.5 g.) mp 335° C. (dec).

EXAMPLE 6310-oxo-N-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno[3,2-d]-pyrimidine-7-carboxamide

A mixture of10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (1.0g, 0.0041 mol) and 1,1'-carbonyldiimidazole (1.35 g, 0.0082 mol) indimethylformamide (10 ml) is heated at 95°-100° C. with stirring undernitrogen for 1.5 hours. 5-Aminotetrazole monohydrate (0.42 g, 0.0041mol) is added and the resulting mixture is heated at 100° C. for 1-5hours. The precipitate is filtered off, washed with tetrahydrofuran andrecrystallized from dimethylformamide to give the product (0.6 g.), mp295°-296° C.

EXAMPLE 64 10-Oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide

A mixture of10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (2.5g, 0.01 mol) and 1,1'-carbonyldiimidazole (1.7 g, 0.01 mol) indimethylformamide (25 ml) is heated at 90°-95° C. for one hour undernitrogen. The solution is cooled in an ice bath and anhydrous ammonia isbubbled through for 15 minutes. The mixture is stirred at ice bathtemperature for 2 hours and at room temperature for one hour. Thereaction mixture is cooled and the precipitate is filtered off. Theprecipitate is washed with tetrahydrofuran and recrystallized fromdimethylformamide to give the product (1.2 g.), mp 319°-320° C.

EXAMPLE 6510-Oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitrile

A mixture of10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide (1.4 g,0.006 mol), p-toluenesulfonyl chloride (1.6 g, 0.008 mol), and pyridine(1.4 ml, 0.017 mol) in dimethylformamide (10 ml) is heated at 95° C. for75 minutes. The mixture is cooled, diluted with water (5 ml) andstirred. The precipitate is filtered, washed with water, with ethanoland dried. Recrystallization from dimethylformamide gives the product(0.8 g.), mp 263°-264° C. (dec).

EXAMPLE 667-(1H-Tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidin-10-one

A mixture of10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitrile (0.6 g.,0.0026 mol), sodium azide (0.56 g., 0.0086 mol) and ammonium chloride(0.46 g., 0.0036 mol) in dimethylformamide (75 ml) is heated at100°-105° C. for 18 hours under nitrogen. The reaction mixture iscooled, poured into ice water (700 ml) and acidified with concentratedhydrochloric acid (1 ml). The precipitate is filtered off, washed withwater, with acetone and dried. Recrystallization from dimethylformamidegives a crystalline product (0.39 g.) mp 300° C. (dec).

EXAMPLE 6710-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrilehydrochloride salt

A mixture of10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide (0.3 g.,0.0012 mol) and thionyl chloride (0.18 ml, 0.0025 mol) indimethylformamide (5 ml) is heated at 70° C. under nitrogen for 4 hours.The reaction mixture is cooled in an ice bath. The product, whichprecipitates, is filtered off and washed with water. Recrystallizationfrom dimethylformamide gives a crystalline product (0.15 g.), mp 294° C.(dec).

EXAMPLE 687-(1H-Tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-10-one

A mixture of10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile (0.058g., 0.0003 mol), sodium azide (0.074 g., 0.0011 mol) and ammoniumchloride (0.061 g., 0.0011 mol) in dimethylformamide (15 ml) is heatedat 95°-100° C. under nitrogen for 46 hours. The solvent is evaporated.The residue is triturated with 1 N hydrochloric acid, filtered andsucked dry to give the product, mp 300° C. (dec).

EXAMPLE 693-Methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylicacid, methyl ester

A mixture of 11.27 g (0.066 mol) of2-amino-4-methyl-3-thiophenecarboxylic acid, methyl ester (ChemischeBerichte, Vol. 98, pages 3571-3577, 1965) and 11.3 g (0.066 mol) of6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader ChemicalCompany) is heated in a wax bath at 173°-190° C. for 220 minutes undernitrogen. The distillate is collected in a Dean-Stark trap attached tothe reaction flask. The mixture is cooled, dissolved in hot methanol,cooled and 0.61 g of3-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylicacid, methyl ester is collected; mp 208°-209° C. after recrystallizationfrom dichloromethane-methanol.

EXAMPLE 702-Ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid,monohydrochloride

To a cooled solution of2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid(Example 2), 0.2 g (0.00073 mol), in 50 ml of 2-propanol, is added aslight excess of a solution of dry hydrogen chloride in 2-propanol.After 10 minutes, 500 ml of anhydrous ether is added to the previoussolution and the precipitate filtered to give 0.1 g of2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid,monohydrochloride; mp 255°-256° C. after recrystallization from2-propanol-ether.

EXAMPLE 712-Ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid,monosodium salt, monohydrate

To a cooled solution of2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid(Example 2), 0.3 g (0.0011 mol) in 20 ml of dimethylacetamide, is added0.35 ml (0.0011 mol) of a 3.2 molar solution of sodium 2-ethylhexanoatein dimethylacetamide. After 15 minutes, 500 ml of ethyl acetate is addedto the previous solution and the precipitate filtered to give 0.15 g of2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid,monosodium salt, monohydrate; mp 388°-390° C.

STARTING MATERIALS

The starting materials employed in the foregoing examples are obtainedby the methods described in the following:

A. 2-Amino-5-butyl-3-thiophenecarboxylic acid, methyl ester

Triethylamine, 150 ml (1.08 mol), is added to a stirred suspension ofmethyl cyanoacetate, 198.18 g (2 mol) and sulfur, 64.12 g (2 mol), in250 ml of dimethylformamide under a nitrogen atmosphere. Hexanal, 200.3g (2 mol), is added dropwise with stirring to this mixture over fiftyminutes while the temperature is maintained at ˜50° C. The solution wasallowed to reach room temperature and then stirred for twenty one hours,poured into 3 L of water and the aqueous layer extracted with 2 L ofether (2 times). The ether layer is separated and washed successivelywith 2 L of water (2 times), 2 L saturated NaCl solution (2 times),dried over anhydrous Na₂ SO₄ and evaporated to give 187 g of2-amino-5-butyl-3-thiophenecarboxylic acid, methyl ester; mp. 62°-63° C.after recrystallization from hexane.

B. 2-Amino-5-propyl-3-thiophenecarboxylic acid, ethyl ester

From 56.5 g (0.5 mol) of ethyl cyanoacetate, 16 g (0.5 mol) of sulfur,50 ml (0.36 mol) of triethylamine, 43 g (0.5 mol) of pentanal and 200 mlof dimethylformamide, following the previous procedure (A) is obtained52 g of 2-amino-5-propyl-3-thiophenecarboxylic acid, ethyl ester; bp125°-135° C. at 200μ.

C. Tetrahydro-2,5-dimethyl-4-oxo-3-thiophenecarboxylic acid, methylester

A mixture of 83 g (0.83 mol) of methyl crotonate (Aldrich ChemicalCompany) and 100 g (0.83 mol) of methyl thiolactate (Helvetica ChimicaActa, Vol. 45, pages 1750-1765, 1962) in 800 ml of toluene is addeddropwise to a stirred suspension of 64.8 g (1.2 mol) of sodium methoxide(Aldrich Chemical Company) in 500 ml of toluene. The suspension isstirred and refluxed for four and one-half hours, cooled, 500 ml ofwater is added and the mixture is made acidic by the addition of glacialacetic acid. The aqueous solution is extracted with toluene. The toluenelayer is separated, washed successively with 200 ml of water, 200 ml ofsaturated sodium bicarbonate solution and 200 ml of water, dried overanhydrous Na₂ SO₄, and the solution evaporated to give 90 g oftetrahydro-2,5-dimethyl-4-oxo-3-thiophenecarboxylic acid, methyl ester;bp 78°-80° C./0.04 mm.

D. Tetrahydro-4-(hydroxyimino)-2,5-dimethyl-3-thiophenecarboxylic acid,methyl ester

Hydroxylamine hydrochloride, 145 g (2.09 mol), and barium carbonate (J.T. Baker Chemical Company), 219.2 g (1.11 mol), are added to a solutionof 89.3 g (0.474 mol) oftetrahydro-2,5-dimethyl-4-oxo-3-thiophenecarboxylic acid, methyl ester(Example C) in 1 L of absolute ethanol. The suspension is stirred andrefluxed for sixteen hours, cooled, filtered through Supercell Hyflo®(Johns-Manville), the filtrate evaporated and the residue dissolved in500 ml of diethyl ether. The diethyl ether solution is washed with 500ml of water (2 times). The diethyl ether layer is separated, dried overanhydrous Na₂ SO₄ and evaporated to give 83.7 g oftetrahydro-4-(hydroxyimino)-2,5-dimethyl-3-thiophene-carboxylic acid,methyl ester as an orange liquid.

E. 4-Amino-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester

A cooled solution of 80 g (0.39 mol) oftetrahydro-4-(hydroxyimino)-2,5-dimethyl-3-thiophenecarboxylic acid,methyl ester (Example D) in 1 L of anhydrous diethyl ether is saturatedwith dry hydrogen chloride over a period of one hour. The solution isstirred and allowed to reach room temperature over fourteen hours. Theresulting precipitate is filtered, dissolved in 200 ml of water,neutralized with concentrated ammonium hydroxide and the aqueoussolution is extracted with 200 ml of diethyl ether. The diethyl ethersolution is washed with 100 ml of water. The diethyl ether layer isseparated, dried over anhydrous Na₂ SO₄ and evaporated to give 34 g of4-amino-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester; mp75°-77° C. after recrystallization from hexane.

F.3,10-Dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid

6-Aminonicotinic acid (10 g., 0.072 mol) [Berichte, 26, 2187,(1893)],methyl 4-oxotetrahydro-thiophene-3-carboxylate (28 g., 0.175 mol)[Monats, Chem., 104, 1520(1973)] and p-toluenesulfonic acid monohydrate(1.0 g) are thoroughly mixed and heated at 170° C. under nitrogen for 75minutes. The distillate is collected in a Dean-Stark trap. The residueis cooled, tritrated with boiling chloroform and filtered to give theproduct as a yellow powder (11.3 g.). Recrystallization fromdimethylformamide gives an analytical sample mp 314°-315° C. (dec).

G. Ethyl3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylate

Ethyl 6-aminonicotinate (2.5 g., 0.015 mol), methyl4-oxotetrahydrothiophene-3-carboxylate (6.2 g., 0.039 mol) andp-toluenesulfonic acid monohydrate (0.25 g) are thoroughly mixed andheated at 155°-160° C. under nitrogen for 90 minutes. The distillate iscollected in a Dean-Stark trap. The residue is cooled, triturated withboiling ethanol and filtered. Recrystallization from methanol givesyellow crystals (1.2 g.), mp 183°-185° C.

H.3,10-Dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid

A suspension of ethyl3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4d]pyrimidine-7-carboxylate(0.25 g., 0.001 mol) in 2 N hydrochloric acid is refluxed for 2.5 hours.The reaction mixture is cooled in an ice-bath. The product is filteredoff and recrystallized from dimethylformamide to give yellow crystals(0.14 g.), mp 311°-312° C.

I. Ethyl3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylate

A mixture of3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylicAcid (15 g., 0.06 mol) and 1,1' carbonyldiimidazole (9.8 g, 0.06 mol) indimethylformamide (12 ml) and tetrahydrofuran (700 ml) is refluxed withstirring for 3 hours. Absolute ethanol (20 ml) is added and refluxing iscontinued for a further 3 hours. The solvents are removed under reducedpressure. The residue is shaken with hot 0.5 mol aqueous sodiumbicarbonate (200 ml), cooled and filtered. The residue is washed severaltimes with water and recrystallized from methanol to give the product(8.9 g.) mp 183°-185° C.

J.3,10-Dihydro-10-oxo-N-1H-tetrazol-5-yl-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide

A mixture of3,10-dihydro-10-oxo-N-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid (1.0 g., 0.004 mol) and 1,1'-carbonyldiimidazole (1.3 g., 0.008mol) in tetrahydrofuran (75 ml) and dimethylformamide (2 ml) is refluxedwith stirring under nitrogen for 1.5 hours. 5-Aminotetrazole monohydrate(0.4 g., 0.004 mol) is added and the resulting mixture is refluxed for 3hous. The reaction mixture is cooled in an ice bath and the product isfiltered off. Recrystallization from dimethylformamide gives the product(0.94 g.), mp 290° L C. (dec).

K.3,10-Dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide

A mixture of3,10-dihydro-10-oxo-1H-pyridol[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid (4.4 g., 0.018 mol) and 1,1'-carbonyldiimidazole (2.9 g., 0.018mol) in tetrahydrofuran (300 ml) and dimethylformamide (4 ml) isrefluxed under nitrogen for 3.5 hours. The solution is cooled in an icebath and anhydrous ammonia is bubbled through for 45 minutes. Theprecipitate is filtered off, washed with hot 0.5 M. aqueous sodiumbicarbonate solution, with hot dimethylformamide with ether and dried togive a yellow powder (2.9 g.). mp 285° C. (dec).

L.3,10-Dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile

A mixture of3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide(2.9 g., 0.012 mol) and thionyl chloride (1.5 ml) in dimethylformamide(30 ml) is heated at 70° C. for 4 hours. The reaction mixture is cooledin an ice bath. The product, which precipitates, is filtered off andwashed with water. Recrystallization from methanol gives a crystallineproduct (1.6 g.), mp 256°-257° C.

M.3,10-Dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine

A mixture of3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile(1.0 g., 0.004 mol), sodium azide (0.81 g., 0.012 mol) and ammoniumchloride (0.69 g., 0.013 mol) in dimethylformamide (150 ml) is heated at100°-105° C. for 18 hours. The solvent is removed at reduced pressure.The residue is triturated with 1 N hydrochloric acid, filtered, washedwith water, dissolved in 10% aqueous potassium carbonate, filtered andreprecipitated with 1 N hydrochloric acid. The solid is filtered off andrecrystallized from dimethylformamide-methanol to give a crystallineproduct (0.96 g.), mp 285° C.

N.3,10-Dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylicacid (I) and3,10-dihydro-10-oxo-1H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid (II)

6-Aminonicotinic acid (7.3 g, 0.053 mol), methyl3-oxotetrahydrothiophene-2-carboxylate (containingmethyl-4-oxotetrahydrothiophene-3-carboxylate) (27.6 g., 0.140 mol) andp-toluenesulfonic acid monohydrate (0.7 g) are thoroughly mixed andheated at 170° C. uner nitrogen for 75 minutes. The distillate iscollected in a Dean-Stark trap. The residue is cooled, triturated withboiling chloroform and filtered to give a mixture of I and II as ayellow powder (10.4 g.), mp 300° C. (dec).

O. Ethyl3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylate(I)and ethyl3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylate(II)

A mixture of3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylicacid (containing3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylicacid) (10.4 g, 0.042 mol) and 1,1' carbonyldiimidazole (6.9 g, 0.042mol) in dimethylformamide (10 ml) and tetrahydrofuran (500 ml) isrefluxed with stirring for 3 hours. Absolute ethanol (20 ml) is addedand refluxing is continued for a further 3 hours. The solvents areremoved under reduced pressure to give a solid product.Recrystallization from 2-propanol gives a mixture of I and II (8.0 g.)mp 147°-149° C.

The mixture is dissolved in a minimum amount of chloroform andfractionated with a Waters preparative High Pressure LiquidChromatography column (silica gel) using ethyl acetate as solvent. I isrecrystallized from isopropyl ether-2-propranol to give yellow crystals(5.3 g.) mp 155°-156° C.

II is recrystallized from methanol to give a crystalline product (0.5g.).

P.3,10-Dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylicacid

A suspension of ethyl3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylate(5.0 g, 0.018 mol) in 2 N hydrochloric acid (60 ml) is refluxed for 3hours. The reaction mixture is cooled in an ice-bath. The precipitate isfiltered, washed with water, with acetone and dried to give the product(3.5 g.), mp 325° C. (dec).

Q.3,10-Dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide

A mixture of3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylicacid (3.0 g., 0.012 mol) and 1,1'-carbonyldiimidazole (2.0 g., 0.012mol) in tetrahydrofuran (180 ml) and dimethylformamide (3.5 ml) isrefluxed under nitrogen for 5 hours. The solution is cooled in anice-bath and anhydrous ammonia is bubbled through for 15 minutes. Themixture is stirred at ice-bath temperature for 2 hours and at roomtemperature for one hour. The reaction mixture is cooled and theprecipitate is filtered off and washed with tetrahydrofuran. Theprecipitate is treated with hot 0.5 mol aqueous sodium bicarbonatesolution, filtered, washed with water, washed with acetone and suckeddry to give the product (2.0 g.), mp 334° C. (dec).

R.3,10-Dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitrile

A mixture of3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide(1.7 g., 0.007 mol), p-toluene-sulfonyl chloride (2.0 g., 0.01 mol) andpyridine (1.7 ml, 0.021 mol) in dimethylformamide (30 ml) is heated at100° C. under nitrogen for 40 minutes. The reaction mixture is cooledand diluted with water (15 ml). The resulting aqueous solution isstirred for one hour. The precipitate is filtered off, washed with waterand sucked dry. Recrystallization from methanol gives the product (1.1g.), mp 261°-263° C.

S.3,10-Dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1.2-a]thieno[3,2-d]pyrimidine

A mixture of3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3.2-d]pyrimidine-7-carbonitrile(0.8 g., 0.003 mol), sodium azide (0.8 g., 0.012 mol) and ammoniumchloride (0.07 g., 0.013 mol) in dimethylformamide (100 ml) is heatedunder nitrogen at 100° C. for 18 hours. The reaction mixture is cooled,poured into ice-water (750 ml), acidified with concentrated hydrochloricacid and stirred for one hour. The precipitate is filtered, washed withwater and with acetone. Recrystallization from dimethylformamide gives acrystalline product (0.63 g.), mp 297° C. (dec).

What is claimed is:
 1. A compound of the formula ##STR32## and saltsthereof, wherein X is --CH₂ -- and X¹ is --CH₂ --, X is --CH₂ CH₂ -- andX¹ is a single bond, and X is a single bond and X¹ is --CH₂ CH₂ --; Z¹is CO₂ lower alkyl, cyclic hydrocarbon, cyano, carboxy, ##STR33## and Rand R¹ are hydrogen, lower alkyl, cyclic hydrocarbon, chloro, bromo,phenyl or x-substituted phenyl were x is lower alkyl, chloro, fluoro,cyclic hydrocarbon-O-, or lower alkyl --O--.
 2. The compound of claim 1having the name3,10-dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine,and salts thereof.
 3. The compound of claim 1 having the name3,10-dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine,and salts thereof.
 4. The compound of claim 1 having the name3,10-dihydro-10-oxo-N-1H-tetrazol-5-yl-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide,and salts thereof.